Kohei Shitara1, Atsuo Takashima2, Kazumasa Fujitani3, Keisuke Koeda4, Hiroki Hara5, Norisuke Nakayama6, Shuichi Hironaka7, Kazuhiro Nishikawa8, Yoichi Makari9, Kenji Amagai10, Shinya Ueda11, Kazuhiro Yoshida12, Hideki Shimodaira13, Tomohiro Nishina14, Masahiro Tsuda15, Yukinori Kurokawa16, Takao Tamura17, Yasutsuna Sasaki18, Satoshi Morita19, Wasaburo Koizumi20. 1. Department of Gastrointestinal Oncology, National Cancer Center Hospital East, Kashiwa, Japan. Electronic address: kshitara@east.ncc.go.jp. 2. Gastrointestinal Medical Oncology Division, National Cancer Center Hospital, Tokyo, Japan. 3. Department of Surgery, Osaka General Medical Center, Osaka, Japan. 4. Department of Surgery, Iwate Medical University School of Medicine, Morioka, Japan. 5. Department of Gastroenterology, Saitama Cancer Center, Saitama, Japan. 6. Department of Gastroenterology, Kanagawa Cancer Center, Yokohama, Japan. 7. Clinical Trial Promotion Department, Chiba Cancer Center, Chiba, Japan. 8. Department of Surgery, National Hospital Organization Osaka National Hospital, Osaka, Japan. 9. Department of Surgery, Sakai City Medical Center, Sakai, Japan. 10. Department of Gastroenterology, Ibaraki Central Hospital, Kasama, Japan. 11. Department of Medical Oncology, Kindai University Nara Hospital, Ikoma, Japan. 12. Department of Surgical Oncology, Gifu University School of Medicine, Gifu, Japan. 13. Department of Clinical Oncology, Tohoku University Hospital, Sendai, Japan. 14. Department of Gastrointestinal Medical Oncology, National Hospital Organization Shikoku Cancer Center, Matsuyama, Japan. 15. Department of Gastroenterological Oncology, Hyogo Cancer Center, Akashi, Japan. 16. Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, Suita, Japan. 17. Department of Medical Oncology, Kindai University Faculty of Medicine, Sayama, Japan. 18. Institute of Molecular Oncology, Showa University School of Medicine, Tokyo, Japan. 19. Department of Biomedical Statistics and Bioinformatics, Kyoto University Graduate School of Medicine, Kyoto, Japan. 20. Department of Gastroenterology, Kitasato University School of Medicine, Sagamihara, Japan.
Abstract
BACKGROUND: Weekly administration of solvent-based paclitaxel is one of the standard second-line chemotherapy regimens for advanced gastric cancer. Nanoparticle albumin-bound paclitaxel (nab-paclitaxel) was developed to improve the solubility of paclitaxel and does not need premedication to avoid infusion-related reactions associated with solvent-based paclitaxel. Additionally, higher doses of nab-paclitaxel can be administered over a shorter infusion time and at higher drug concentrations compared with solvent-based paclitaxel. We aimed to investigate the efficacy and safety of nab-paclitaxel versus solvent-based paclitaxel in patients with previously treated advanced gastric cancer. METHODS: We did a randomised, open-label, non-inferiority, phase 3 trial at 72 institutions in Japan. Patients aged 20 years or older with advanced gastric adenocarcinoma refractory to a fluoropyrimidine-containing first-line chemotherapy regimen, with progressive disease or a relapse fewer than 24 weeks after the final dose of adjuvant chemotherapy were randomly assigned (1:1:1) to receive intravenous nab-paclitaxel (260 mg/m2) every 3 weeks (on day 1 of a 21-day cycle), weekly nab-paclitaxel (100 mg/m2, on days 1, 8, and 15 of a 28-day cycle), or weekly solvent-based paclitaxel (80 mg/m2, on days 1, 8, and 15 of a 28-day cycle). Randomisation was done with the minimisation method, with stratification for previous use of docetaxel, presence of peritoneal metastases, and Eastern Cooperative Oncology Group (ECOG) performance status. The primary endpoint was overall survival in the full analysis set, which included all randomly assigned patients who received at least one dose of study drug, with a non-inferiority margin of 1·25 for the hazard ratio. This trial is registered with Japan Pharmaceutical Information Center Clinical Trial, number JapicCTI-132059, and has been completed. FINDINGS:Between March 13, 2013, and May 14, 2015, 741 patients were randomly assigned to nab-paclitaxel every 3 weeks (n=247), weekly nab-paclitaxel (n=246), or weekly solvent-based paclitaxel (n=248). Median follow-up for overall survival was 9·99 months (IQR 6·05-15·05). Median overall survival was 10·3 months (95% CI 8·7-11·4) in the group that received in the nab-paclitaxel every 3 weeks, 11·1 months (9·9-13·0) in the weekly nab-paclitaxel group, and 10·9 months (9·4-11·8) in the weekly solvent-based paclitaxel group. Weekly nab-paclitaxel was non-inferior to weekly solvent-based paclitaxel (hazard ratio 0·97, 97·5% CI 0·76-1·23; non-inferiority one-sided p=0·0085), whereas nab-paclitaxel every 3 weeks was not non-inferior to solvent-based paclitaxel (1·06, 95% CI 0·87-1·31; non-inferiority one-sided p=0·062). The main grade 3 or worse adverse drug reactions were neutropenia (158 [65%] of 244 patients in the group that received nab-paclitaxel every 3 weeks vs 99 [41%] of 241 patients in the weekly nab-paclitaxel group vs 71 [29%] of 243 patients in the weekly solvent-based paclitaxel group), peripheral sensory neuropathy (49 [20%] vs six [2%] vs six [2%]), and febrile neutropenia (30 [12%] vs seven [3%] vs two [1%]). Hypersensitivity reactions were less frequent with nab-paclitaxel every 3 weeks (two [1%] patients) and weekly nab-paclitaxel (three [1%] patients) than with weekly solvent-based paclitaxel (13 [5%] patients). Four treatment-related deaths were reported overall (pneumonia in one patient in the group that received nab-paclitaxel every 3 weeks, febrile neutropenia/pneumonia in one patient, and septic shock in one patient in the weekly nab-paclitaxel group, and respiratory disease/interstitial lung disease in one patient in the weekly solvent-based paclitaxel group). INTERPRETATION: As the trial showed that weekly nab-paclitaxel was non-inferior to weekly solvent-based paclitaxel in terms of overall survival, the advantages of the nab-paclitaxel formulation make it a potential regimen for second-line treatment of gastric cancer. FUNDING: Taiho Pharmaceutical.
RCT Entities:
BACKGROUND: Weekly administration of solvent-based paclitaxel is one of the standard second-line chemotherapy regimens for advanced gastric cancer. Nanoparticle albumin-bound paclitaxel (nab-paclitaxel) was developed to improve the solubility of paclitaxel and does not need premedication to avoid infusion-related reactions associated with solvent-based paclitaxel. Additionally, higher doses of nab-paclitaxel can be administered over a shorter infusion time and at higher drug concentrations compared with solvent-based paclitaxel. We aimed to investigate the efficacy and safety of nab-paclitaxel versus solvent-based paclitaxel in patients with previously treated advanced gastric cancer. METHODS: We did a randomised, open-label, non-inferiority, phase 3 trial at 72 institutions in Japan. Patients aged 20 years or older with advanced gastric adenocarcinoma refractory to a fluoropyrimidine-containing first-line chemotherapy regimen, with progressive disease or a relapse fewer than 24 weeks after the final dose of adjuvant chemotherapy were randomly assigned (1:1:1) to receive intravenous nab-paclitaxel (260 mg/m2) every 3 weeks (on day 1 of a 21-day cycle), weekly nab-paclitaxel (100 mg/m2, on days 1, 8, and 15 of a 28-day cycle), or weekly solvent-based paclitaxel (80 mg/m2, on days 1, 8, and 15 of a 28-day cycle). Randomisation was done with the minimisation method, with stratification for previous use of docetaxel, presence of peritoneal metastases, and Eastern Cooperative Oncology Group (ECOG) performance status. The primary endpoint was overall survival in the full analysis set, which included all randomly assigned patients who received at least one dose of study drug, with a non-inferiority margin of 1·25 for the hazard ratio. This trial is registered with Japan Pharmaceutical Information Center Clinical Trial, number JapicCTI-132059, and has been completed. FINDINGS: Between March 13, 2013, and May 14, 2015, 741 patients were randomly assigned to nab-paclitaxel every 3 weeks (n=247), weekly nab-paclitaxel (n=246), or weekly solvent-based paclitaxel (n=248). Median follow-up for overall survival was 9·99 months (IQR 6·05-15·05). Median overall survival was 10·3 months (95% CI 8·7-11·4) in the group that received in the nab-paclitaxel every 3 weeks, 11·1 months (9·9-13·0) in the weekly nab-paclitaxel group, and 10·9 months (9·4-11·8) in the weekly solvent-based paclitaxel group. Weekly nab-paclitaxel was non-inferior to weekly solvent-based paclitaxel (hazard ratio 0·97, 97·5% CI 0·76-1·23; non-inferiority one-sided p=0·0085), whereas nab-paclitaxel every 3 weeks was not non-inferior to solvent-based paclitaxel (1·06, 95% CI 0·87-1·31; non-inferiority one-sided p=0·062). The main grade 3 or worse adverse drug reactions were neutropenia (158 [65%] of 244 patients in the group that received nab-paclitaxel every 3 weeks vs 99 [41%] of 241 patients in the weekly nab-paclitaxel group vs 71 [29%] of 243 patients in the weekly solvent-based paclitaxel group), peripheral sensory neuropathy (49 [20%] vs six [2%] vs six [2%]), and febrile neutropenia (30 [12%] vs seven [3%] vs two [1%]). Hypersensitivity reactions were less frequent with nab-paclitaxel every 3 weeks (two [1%] patients) and weekly nab-paclitaxel (three [1%] patients) than with weekly solvent-based paclitaxel (13 [5%] patients). Four treatment-related deaths were reported overall (pneumonia in one patient in the group that received nab-paclitaxel every 3 weeks, febrile neutropenia/pneumonia in one patient, and septic shock in one patient in the weekly nab-paclitaxel group, and respiratory disease/interstitial lung disease in one patient in the weekly solvent-based paclitaxel group). INTERPRETATION: As the trial showed that weekly nab-paclitaxel was non-inferior to weekly solvent-based paclitaxel in terms of overall survival, the advantages of the nab-paclitaxel formulation make it a potential regimen for second-line treatment of gastric cancer. FUNDING: Taiho Pharmaceutical.
Authors: Xin Luan; Hebao Yuan; Yudong Song; Hongxiang Hu; Bo Wen; Miao He; Huixia Zhang; Yan Li; Feng Li; Pan Shu; Joseph P Burnett; Nathan Truchan; Maria Palmisano; Manjunath P Pai; Simon Zhou; Wei Gao; Duxin Sun Journal: Biomaterials Date: 2021-06-03 Impact factor: 12.479